What is the mechanism of action of muscle relaxants?

Mechanism of Action of Muscle Relaxants

Central Nervous System Depression

Most skeletal muscle relaxants do not directly relax skeletal muscle fibers and instead work through general central nervous system (CNS) depression, with no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber. 1, 2

• The mechanism of action for most oral muscle relaxants remains poorly defined, with effects measured mainly by subjective responses rather than objective muscle relaxation. 2
• These agents produce nonspecific sedation rather than true muscle relaxation, which explains why their clinical efficacy is difficult to distinguish from general CNS depressant effects. 2, 3

Agent-Specific Mechanisms

Alpha-2 Adrenergic Agonists (Tizanidine, Baclofen)

• Tizanidine is an α2-adrenergic receptor agonist that reduces spasticity by increasing presynaptic inhibition of motor neurons, with greatest effects on polysynaptic pathways in the spinal cord. 4
• Tizanidine has no direct effect on skeletal muscle fibers or the neuromuscular junction and no major effect on monosynaptic spinal reflexes. 4
• The overall effect reduces facilitation of spinal motor neurons through central mechanisms. 4
• Baclofen functions as a GABA-B agonist with documented efficacy for muscle spasm and spasticity, particularly in CNS injury and neuromuscular disorders, working through spinal mechanisms. 5, 6
• Baclofen may have a spinal action that suppresses excitability of spinal pathways to abdominal muscle motoneurons, representing a muscle relaxant with spinal rather than brainstem action. 7

Sarcoplasmic Reticulum Calcium Release Inhibitors (Dantrolene)

• Dantrolene produces relaxation by affecting the contractile response of muscle at a site beyond the myoneural junction, dissociating excitation-contraction coupling by interfering with calcium release from the sarcoplasmic reticulum. 8
• This is the only muscle relaxant that acts directly on skeletal muscle tissue rather than through CNS mechanisms. 8
• Dantrolene inhibits calcium release from the sarcoplasmic reticulum, reestablishing myoplasmic calcium equilibrium in conditions like malignant hyperthermia. 8

Tricyclic-Related Agents (Cyclobenzaprine)

• Cyclobenzaprine is structurally related to tricyclic antidepressants and mediates effects centrally via inhibition of tonic somatic motor function, likely through modulation of noradrenergic and serotonergic systems. 9
• Cyclobenzaprine exhibits low nanomolar affinity for histamine H1 receptors and acts as a potent noncompetitive antagonist, which explains its significant sedative effects in over 30% of patients. 9
• This off-target H1 receptor antagonism facilitates the drowsiness and sedative-hypnotic effects commonly seen with cyclobenzaprine use. 9

Agents with Unclear Mechanisms (Methocarbamol, Metaxalone, Carisoprodol)

• Methocarbamol's mechanism has not been established in humans but may be due to general CNS depression, with no direct action on the contractile mechanism of striated muscle, motor end plate, or nerve fiber. 1
• Metaxalone, carisoprodol, orphenadrine, and chlorzoxazone all work through poorly defined central mechanisms, producing nonspecific CNS depression rather than direct muscle effects. 10, 2
• Orphenadrine has anticholinergic properties similar to diphenhydramine, contributing to its CNS effects including confusion and anxiety. 5, 11

Clinical Implications of Mechanism

• The lack of direct muscle action explains why these agents have limited efficacy in chronic pain conditions and why their effects are primarily measured through subjective patient responses. 2, 3
• All skeletal muscle relaxants carry CNS adverse effects, primarily sedation, as a class characteristic with no compelling evidence that any agent differs significantly in this regard. 11
• The central mechanisms of action result in additive effects when combined with other CNS depressants, including opioids and benzodiazepines, substantially increasing risks of respiratory depression and death. 7

Neuromuscular Junction Blockers (Anesthesia Context)

• Succinylcholine is a unique analogue of acetylcholine that binds to nicotinic receptors at the neuromuscular junction, causing prolonged depolarization followed by muscle paralysis through a peripheral mechanism. 7
• Non-depolarizing agents like rocuronium and atracurium block nicotinic receptor activity at the neuromuscular junction without causing depolarization. 7
• These neuromuscular blocking agents are used in anesthesia for intubation and have entirely different mechanisms than oral muscle relaxants used for spasticity or musculoskeletal pain. 7